Asthma is a chronic inflammatory condition of the airways characterised by reversible airway obstruction, and has traditionally been classified as extrinsic (due to allergic reaction to inhaled allergens such as pollens and house dust mite) or intrinsic (not due to classical allergy), the mechanism for which is unknown. This latter form of asthma has been called “idiopathic” asthma
In a recently reported study based on diagnosed asthma subjects, asthma was classified based on differences in eosinophil and neutrophil counts in sputum (Simpson et al., Inflammatory subtypes in asthma: Assessment and identification using induced sputum, Respirology 2006; 11, 54-61). The subjects in the study were divided into different asthma subtypes based on the presence of these cell types compared to healthy control subjects. Several asthma sub-types were identified including neutrophilic asthma (>61% neutrophils) and eosinophilic asthma (>1.01% eosinophils). The neutrophilic asthma group comprised approximately 20% of the overall number of asthmatics. The study further reported persistent neutrophilia in the majority of these subjects over both short term (4 week) and long term (mean 5.3 years) intervals between sampling despite no subject reporting respiratory tract infection during the month prior to assessment. While subjects with asthma were found to have higher levels of intracellular bacteria and macrophages than healthy controls, no significant differences were found between neutrophilic asthmatics and the other asthma groups. Indeed, the levels of bacteria found were stated to be less than that consistent with acute bacterial infections, and the report concluded there was no evidence of bacterial infection to explain the inflammatory process of neutrophilic asthma.
Non-typable Haemophilus influenzae (NTHi) is the most common pathogenic bacteria associated with chronic bronchitis (CB) (Sethi S, Murphy T F, Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art review, Clin Microbiol Rev 2001; 14: 336-363). NTHi can be found in the upper airways (eg., nose, middle ear, throat and sinuses) of healthy individuals and patients with CB (Sethi, 2001) as well as several locations of the respiratory tract, including the lumen, adhering to mucosal epithelial cells in the interstitium of the submucosa (Moller et al., Haemophilus influenzae in lung explants of patients with end-stage pulmonary disease, Am J Respir Crit Care Med 1998; 157: 950-56). Studies of non-obstructive and obstructive CB have observed that a large proportion of patients have persistent infection with NTHi (Murphy T F, Bartos L C, Purification and analysis with monoclonal antibodies of P2, the major outer membrane protein of nontypable Haemophilus influenza, Infect Immun 1988; 56:1084-89).
Both NTHi and Staphylococcus aureus have previously been shown to induce non-IgE-mediated and enhanced IgE-mediated histamine release from mast cells obtained by broncheoalveolar lavage from the airways of patients with CB. In the case of NTHi, it has been reported that exotoxin may be responsible for the enhancement of IgE-mediated histamine release (Clementsen et al., Endotoxin from Haemophilus influenzae enhances IgE-mediated and non-immunological histamine release, Allergy 1990; 45: 10-17). Immune cells isolated from patients with CB during acute exacerbations have been shown to be both sensitized and hyperactive to the patient's own bacteria (Norn et al., Bacteria-induced IgE-mediated histamine release: Examination of patients with chronic bronchitis (CB) during acute exacerbations. Agents Actions 41, Special Conference Issue 1994: C22-C23). Several studies have also reported specific IgE antibodies produced in response to respiratory infection by fungi (e.g., Aspergillus) and viruses, (e.g., respiratory syncytial virus, parainfluenza virus), (Welliver et al., Role of parainfluenza virus-specific IgE in pathogenesis of croup and wheezing subsequent to infection. J Pediatrics 1982; 101: 889-96) and bacteria (e.g., S. Pneumoniae (Kjaergard et al., Basophil-bound IgE and serum IgE directed against Haemophilus influenzae and Streptococcus pneumoniae in patients with chronic bronchitis during acute exacerbations, APMIS 1996; 104: 61-67; Tee R D, Pepys J., Specific IgE serum antibodies to bacterial antigens in allergic lung disease, Clin Allergy 1982; 12: 439-50; Pauwels et al., IgE antibodies to bacteria with bronchial asthma, Allergy 1980; 157: 665-9) S. aureus (Rhode et al., Increased IgE-antibodies to Staphylococcus aureus enterotoxins in patients with COPD. Respir Med 2004; 98: 858-64; Tee, 1982), Pseudomonas aeruginosa (Shen et al., Specific Pseudomonas immunoglobulin E antibodies in sera of patients with cystic fibrosis. Infect Immun 1981; 32: 967-68), and Mycoplasma pneumoniae (Seggev et al., Isotype-specific antibody responses to acute Mycoplasma pneumoniae infection. Ann Allergy Asthma Immunol 1996; 77: 67-73)). IgE antibodies specific for NTHi have also been identified in the serum of patients with CB (Kjaergard, 1996; Tee 1982) and cystic fibrosis (Tee, 1982).
In a study of patients with bronchial asthma, IgE antibodies to NTHi were found in 29%. Antibodies to NTHi and/or Streptococcus pneumoniae were also present in 22% of patients with no other IgE mediated hypersensitivity. However, higher levels of IgE bacterial antibodies were found in patients with demonstrable IgE antibodies to various inhalant antigens (suggesting an allergic phenotype) (Pauwels, 1980). While it has been hypothesised that bacterial infections may play a role in the induction and exacerbation of asthma, it has been considered that exacerbation of asthma is predominantly triggered by viral infection. Indeed, the clinical effect of bacterial vaccines in the treatment of asthma has been questioned leading to international (WHO) recommendations that bacterial vaccines have no role in modern asthma treatment.
Despite massive amounts of research focused on therapeutic asthma intervention and treatment, the condition remains a major, costly and growing problem in modern Westernised societies.